Current understanding of the cellular processes implicated in the maturation, homeostasis and repair of the human heart is extremely deficient and the need for basic information is striking. Findings in nematodes, fruit flies, zebra fish and rodents have often been translated to human beings with little caution, emphasizing the necessity to study the fundamental principles that regulate the plasticity of the myocardium during the lifespan of women and men. Moreover, the mechanisms modulating the response of the female and male heart to ischemic and non-ischemic myocardial injury and the principal factors conditioning end-stage heart failure and death in humans are at present unknown. This may explain why the astonishing advancements made in cardiac biology experimentally have had so far little impact on the management of the human disease. Thus, the major objectives of this application are: a) To define the contribution of human cardiac stem cells (hCSCs) to the physiological growth of the heart postnatally;b) To establish the rate of myocyte and non-myocyte turnover mediated by hCSC activation and differentiation, together with the analysis of the functional properties of myocytes, in the developing, adult, aging and failing heart;and c) To identify the role of hCSCs in the aging myopathy and heart failure to answer the question whether ventricular decompensation is a stem cell disease. To achieve these goals, we will employ five distinct protocols: a) Retrospective 14C birth dating of cardiac cells to establish the average age of myocytes and non-myocytes;b) A mathematical model of age- structured cell populations to define the age distribution of myocytes and non-myocytes;c) A mathematical model of hierarchically organized cells to assess the rate of formation of myocytes and non-myocytes by lineage commitment of hCSCs;d) hCSC and myocyte senescence by the expression of p53 and p16INK4a, and the accumulation of DNA damage and telomere dysfunction induced foci (TIFs) to determine the integrity of the telomere-telomerase axis;and e) The mechanical, electrical and calcium transient characteristics of myocytes to evaluate the effects of parenchymal cell physiology on ventricular hemodynamics. These five sets of complementary data will offer a novel comprehensive perspective of the cellular processes which govern the lifespan of the human heart. This information is critical for the recognition of the mechanisms that control the dynamics of the human heart, its reserve, adaptation to stress and failure. PUBLIC HEALTH RELEVANCE: The documentation that the human heart contains a population of stem cells that regulate myocardial growth in health and disease may have important clinical implications. Stem cell therapy may be prospected as a novel therapeutic strategy for the failing heart.